1. Field of the Invention
The present invention relates to an external dermatological composition containing an anti-inflammatory drug ketoprofen. More specifically, it relates to an external dermatological composition having a remarkably enhanced percutaneous absorption realized by incorporating ketoprofen in a specific (meth)acrylic copolymer.
2. Description of the Related Art
Ketoprofen (3-Benzoylhydratropic acid), a non-steroidal anti-inflammatory drug, was developed in 1967, and is useful for the treatment of rheumatoid arthritis, osteoarthrosis, low back pains, neuralgia, trauma, postoperation, acute upper respiratory tract infection, and is widely used in peroral capsules, suppositories, and intramuscular injection agents.
Generally, however, the capsules, suppositories, and intramuscular agents containing this drug have a relatively short acting time of only 4 to 6 hours, and it is reported that problems arise such as an insufficient effect at a topical afflicted site having pain or gastroenteric disorders, or rarely, side effects such as low body temperature shock. Furthermore, it is believed that these problems arising from the use of capsules, suppositories, and intramuscular agents can be effectively solved by a percutaneous absorption of the drugs (see Ther. Res. 3(6), 1099 (1985)).
In addition, it is reported that a percutaneous absorption of drugs has an intimate correlationship with liposolubility and the percutaneous absorption of a series of non-steroid type anti-inflammatory drugs shows a parabolic correlationship with a partition coefficient rate of a drug between water and octanol. Ketoprofen in particular has a good partition balance between water and octanol (i.e., good hydrophilicity and lipophilicity balance and high percutaneous absorption (see Life Science, 39(12), 1043 (1986)).
In view of the above background, to enable the excellent antiflammatory activity possessed by ketoprofen to be exhibited topically, and at the same time to alleviate systemic side effects, ointments and poultices were recently developed and employed for the therapy of acute diseases having relatively light symptoms, such as tendovagnitis, peritendinitis, epicondylitis lateral, and myalagia, and for an improvement of the therapeutical effect of chronic diseases by using a combination of capsules and suppositories.
To enable such a topical percutaneous absorptive agent to exhibit the desired treatment effect, the problem is how to migrate the drug effectively from the preparations into the skin, and further into the subcutaneous muscle, synovia, or synovial membrane located under the skin. As far as the present inventor are aware, in currently available commercial ointments and poultices, the drug absorption through the skin is low: For example, the excreted ratios in urine, usually taken as an index of absorption, are 2.1% of the dosage in the case of ointments and 4.7% of the dosage in the case of poultices, which are about 1/35 to 1/15 compared with the 70% of those of the capsules or suppositories.
Furthermore, concerning the drug concentration in blood, the C.sub.max of ointments is 150 ng/ml in the case of a 300 mg dosage and the C.sub.max of poultices is 43 ng/ml in the case of a 30 mg dosage, which are remarkably low when compared with the C.sub.max of 6000 ng/ml of capsules (dosage=75 mg).
On the other hand, widespread studies have been made of percutaneous absorption promoting substances, which are intended to enhance the drug diffusibility through the skin by using a chemical substance.
According to the knowledges of the present invention, as attempts to enhance the percutaneous absorption of ketoprofen in ointments, and poultices, there have been proposed a method in which a solution thereof dissolved in peppermint oil is formulated in an ointment (Japanese Unexamined Patent Publication (Kokai) No. 58-29706), a method in which ketoprofen is formulated in an ointment together with fatty acid esters, waxes, surfactants, and hydrocarbons (Japanese Unexamined Patent Publication (Kokai) No. 58-39616), and a method in which ketoprofen is formulated in an ointment together with higher alcohols, hydrocarbons, and emulsifiers (Japanese Unexamined Patent Publication (Kokai) No. 58-103311), etc.
According to these methods, however, the drug migration ratio to the skin is only 14 to 20% of the drug dosage, and a satisfactory absorption thereof cannot be obtained.
Also, proposals have been made for a poultice containing a basic amino acid formulated therein (Japanese Unexamined Patent Publication (Kokai) No. 57-81409) and a poultice having an emulsifier and a dissolving aid added therein (Japanese Unexamined Patent Publication (Kokai) No. 61-275212), but these provide only a 2-fold enhancement of the drug absorption compared to that where there is no addition, and thus do not give a satisfactory effect.
Accordingly, the percutaneous absorption of ketoprofen is low for ointments and poultices, and thus a satisfactory therapeutical effect on a disease in a portion deep beneath the skin cannot be obtained, and further, substantially no effect on systemic diseases is exhibited.
On the other hand, a tape agent comprising a pressure sensitive adhesive composed mainly of a (meth)acrylic copolymer laminated on a plastic film support is thought to be an effective means of enhancing the percutaneous absorption of a drug, for the reasons given below, and studies have been made of this subject with regard to a large number of drugs, including ketoprofen:
(1) nonionic type molecular species, which migrate into skin better than ionic type molecular species, have a higher solubility in a tape than in ointments and poultices;
(2) since the base (adhesive layer) thickness is only about 10 .mu.m, the diffusion distance for the drug is shorter than in poultices;
(3) the tape has a occlusive effect obtained through the support and the tackifier layer;
(4) since the tape is flexible and has a stronger adhesive power than poultices, it can be used for plastering at a curved site which is subjected to a large amount of movement, such as a joint;
To enhance the percutaneous absorption of the (meth)acrylic adhesive tape agent, the following points must be observed:
(1) an adhesive base must be used in which the drug is highly soluble and diffusibile;
(2) a nonionic drug must be formulated in as high a concentration as possible; and
(3) the base thickness must be as thin as possible while maintaining a sufficient adhesion to the skin.
Further, with regard to the adhesive, the following requirements must be met:
(4) it must be chemically inert to the drug;
(5) there must be no change with a lapse of time of the drug releasability and adhesion to the skin; and
(6) it must have a low irritation of the skin.
As a method for enhancing the drug concentration in the base, there have been proposed:
(i) a method in which an adhesive layer containing a drug at a saturated solubility or higher is laminated on a support to which the drug can migrate (Japanese Patent Publication (Kokoku) No. 60-59207;
(ii) a method in which the surface layer of a support to which the drug can migrate is crosslinked, and an adhesive layer containing a drug at a saturated solubility or higher is laminated thereon (Japanese Unexamined Patent Publication (Kokai) No. 59-172418);
(iii) a method in which a drug is contained at a saturated solubility or higher in an adhesive layer, and the drug in the supersaturated portion is uniformly dispersed therein in the form of fine particles (Japanese Unexamined Patent Publication (Kokai) No. 60-185713);
(iv) a method in which a drug is contained at a saturated solubility or higher in an adhesive layer in which fine particles of an acrylic polymer are dispersed (Japanese Unexamined Patent Publication (Kokai) No. 61-148117); and,
(v) a method in which a drug solution in a good solvent for that drug is added to an adhesive solution in a poor solvent for that drug, to prepare a dispersion of fine particles of the drug, and the layer containing same is laminated on a support (Japanese Unexamined Patent Publication (Kokai) No. 62-273913); etc.
According to these methods, however, fine crystals of the drug dispersed in the adhesive layer will grow during storage, and thus problems arise such as a loss of drug releasability or a lowered adhesion to the skin.
To make the base layer thinner, the following methods have been proposed:
(i) a method in which an adhesive layer not containing the drug is provided on a support, and an adhesive layer containing the drug is applied thereover (Japanese Examined Patent Publication (Kokoku) No. 60-5569);
(ii) a method in which a drug is coated on the surface by which the adhesive layer is adhered to the skin, uniformly and sparsely over a predetermined area (Japanese Unexamined Patent Publication (Kokai) No. 58-38212);
(iii) a method in which adhesive layers having different drug contents are laminated on a support (Japanese Unexamined Patent Publication (Kokai) No. 59-84817); and
(iv) a method in which an adhesive is coated on a support, and then a drug is coated thereon (Japanese Unexamined Patent Publication (Kokai) Nos. 55-160716, 55-164623, 59-227820).
According to these methods, in the production of the tape preparations, drugs exist in a limited portion of the surface or near the surface of the adhesive layer, but are naturally diffused throughout the whole adhesive layer during storage, and thus the problem of a lowered absorption arise.
As a method of enhancing the absorption of ketoprofen by using an additive substance, there have been proposed a method in which a keratin soluble enzyme (Japanese Unexamined Patent Publication (Kokai) No. 61-28231, a N-acylsarcosine (Japanese Unexamined Patent Publication (Kokai) No. 62-96430), an aliphatic monoalkylolamide (Japanese Unexamined Patent Publication (Kokai) No. 62-103015), or an organic acid (Japanese Unexamined Patent Publication (Kokai) No. 62-126119), is added.
Nevertheless, although examples of the subject drugs are given in the specification, there is no explanation of the absorption of ketoprofen, and the effect thereof is only to provide a 2-fold enhancement of the absorption of an antiinflammatory drug having a similar effect (e.g., indomethacin and fenoprofen), or a 10 to 15% enhancement of the drug skin migration ratio.
Further, to enhance the drug releasability from the adhesive layer and promote the percutaneous absorption, methods have been disclosed in which glycols such as polyethylene glycols, hydrocarbons such as fluid paraffins, and phthalic acid type plasticizers are added (see Japanese Patent Publication (Kokoku) Nos. 58-23366, 59-6285, 61-59607 and Japanese Unexamined Patent Publication (Kokai) Nos. 57-7413, 59-175418, 60-123417, 62-230715). But these additives not only exhibit no effect unless added in large amounts, but also exhibit a plasticizing effect of the adhesive, resulting in a lowering of the adhesive force.
Therefore, although ketoprofen has an excellent antiinflammatory activity, a technique for permitting the amount of drug necessary for exhibiting a higher topical action or systemic action to be effectively percutaneously absorbed through the skin has not been established.
The absorption of a drug is most affected by the physical properties of the adhesive as the drug supply layer, and it is important to find an adhesive having an excellent solubility, diffusibility, and partition coefficient to the skin, of a drug.
Here, the solubility, diffusibility, and partition coefficient to the skin of a drug are properties antagonistic to each other. For example, in a base with a low solubility of a drug, the diffusibility (Dv) and partition coefficient to the skin (K) become higher, but the drug concentration (Cv) is lowered. Conversely, in a base with a high solubility of a drug, the Cv becomes higher but the Dv and K are lowered.
Therefore, an adhesive having a good balance between the Cv and Dv and K, which balance depends on the physical properties of the subject drug (e.g., molecular structure, electrostatic potential, lipid solubility melting point and others, must be selected), and each drug must be individually examined (see "Development Manual of Percutaneously Applied Preparations (1985)").
As conventional (meth)acrylic acopolymers proposed as the adhesive for tape agent, known to the present inventors, there have been proposed:
(i) copolymers of alkyl acrylates having C.sub.4 or higher alkyl groups and acrylic acid (Japanese Patent Publication (Kokoku) No. 52-31405);
(ii) copolymers of alkyl acrylates having C.sub.4 or higher alkyl groups, vinyl acetate or methyl methacrylate, and (meth)acrylic acid and polyfunctional compounds containing 2 or more double bonds in one molecule (Japanese Patent Publication (Kokoku) No. 59-3965); and
(iii) copolymers of alkyl (meth)acrylates having C.sub.4-12 alkyl groups, at least one monomer selected from the group consisting of alkyl (meth)acrylates having C.sub.1-3 alkyl groups, vinyl acetate and styrene, and .alpha.,.beta.-unsaturated carboxylic acids (Japanese Unexamined Patent Publication (Kokai) No. 60-252412).
The solubility of ketoprofen in these adhesives, however, is limited to about 5% by weight, and thus a problem arises of a low percutaneous absorption.
On the other hand, to enhance the solubility of a drug in the adhesive, (meth)acrylic copolymers comprising polar monomers as mentioned below have been proposed as the component to be copolymerized:
(i) a (meth)acrylate having an ether group in molecule (Japanese Patent Publication (Kokoku) Nos. 58-23846, 59-7687, 59-7689, 61-26967, Japanese Unexamined Patent Publication (Kokai) No. 62-77316);
(ii) a vinyl alkyl ether (Japanese Patent Publication (Kokoku) Nos. 61-59607, 62-21395);
(iii) a vinyl compound having an amide bond in molecule (Japanese Unexamined Patent Publication (Kokai) Nos. 59-181214, 60-161917);
(iv) a (meth)acrylamide derivative having an amino group (Japanese Unexamined Patent Publication (Kokai) No. 62-228008); and
(v) a (meth)acrylate of polyoxyalkylene glycol (Japanese Unexamined Patent Publication (Kokai) No. 61-33114).
The adhesives containing these monomers have an excellent ketoprofen solubility, and crystals are not precipitated when the drug is formulated in an amount of about 40% by weight. Nevertheless, because the ketoprofen solubility is very high, the drug migration to the skin is as low as 15 to 20%, and thus a satisfactory absorption cannot be obtained.
Therefore, the problem to be solved by the present invention is to find a (meth)acrylic copolymer having the best ketoprofen solubility, diffusibility, and partition coefficient to the skin.